Regulation of Lymphocyte Development by HLH Proteins

HLH 蛋白对淋巴细胞发育的调节

• 批准号: 8638491
• 负责人: BARBARA L. KEE
• 金额: $ 38.39万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-15 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638491
• 关键词: Affect; Alleles; Applications Grants; B-Lymphocytes; Biological Assay; Bone Marrow; Cell Lineage; Cell Maturation; Cell Survival; Cell physiology; Cells; Commit; Data; Dendritic Cells; Development; E protein; Effector Cell; Event; Failure; Gene Deletion; Gene Expression; Genes; Genetic Transcription; Goals; Granzyme; Helix-Turn-Helix Motifs; ITGAM gene; Immune; Immune response; Immune system; Immunologic Memory; Immunotherapy; In Vitro; Inflammatory; Intervention; Lymphocyte; Lymphoid; Maintenance; Malignant - descriptor; Malignant Neoplasms; Memory; Modeling; Molecular; Multipotent Stem Cells; Mus; Natural Killer Cells; Outcome; Play; Population; Process; Production; Proteins; Regulation; Research; Role; Signal Pathway; Signaling Protein; Specific qualifier value; Stress; T cell differentiation; T-Cell Development; T-Lymphocyte Subsets; TCF3 gene; Tamoxifen; Testing; Therapeutic; Therapeutic Intervention; Transplantation; Virus; Virus Diseases; adaptive immunity; base; cancer cell; cancer immunotherapy; cell transformation; cytokine; gene function; helix-loop-helix protein differentiation inhibitor; in vivo; inhibitor/antagonist; insight; killings; leukemogenesis; mRNA Expression; novel; prevent; progenitor; protein E; protein expression; protein function; public health relevance; recombinase; research study; response; transcription factor; tumor

Project Summary Natural killer (NK) cells play an important role in the immune response to viral infection and in the eradication of stressed or transformed cells. They can also influence adaptive immune responses through production of inflammatory cytokines and modulation of dendritic cell function. Their ability to kill transformed cells and influence adaptive immunity has made them an attractive candidate for tumor immunotherapy. However, our understanding of the mechanisms controlling NK cell development and function are inadequate to allow us to predict the outcome of therapeutic manipulations on NK cell response. My research is focused on understanding the molecular mechanisms controlling innate and adaptive lymphocyte development with an emphasis on the E protein helix-loop-helix transcription factors and their antagonists that Id proteins. Id2 is critical for NK cell development but how it functions and whether it is required for proper NK cell maturation and function has remained elusive We will test the hypothesis that Id2 is required for the terminal maturation of mature (m)NK cells and therefore influences the response of NK cells to virus infection thus limiting immunologic memory in the NK cell population. We hypothesize that Id2 functions to limit E protein activity sufficiently to restrain their potential for differentiation toward alternative lymphocyte fates yet allows E proteins to activate a subset of T cell-associated signaling proteins that are required in a subset of mNK cells. We will determine the molecular mechanism by which the E proteins, which are inhibited by Id2, function to alter the fate and function of NK lineage cells. Our studies will allow us to place the functions of E proteins and Id2 into the larger network of transcriptional regulators that control NK cell development and function and will contribute to our understanding of how therapeutic interventions will influence NK cell responses.

项目摘要 自然杀伤（NK）细胞在病毒感染的免疫应答中起重要作用 以及根除应激或转化细胞。它们也会影响适应性 通过产生炎性细胞因子和调节 树突状细胞功能它们杀死转化细胞并影响适应性的能力 免疫性使它们成为肿瘤免疫治疗的有吸引力的候选者。然而，在这方面， 我们对控制NK细胞发育和功能的机制的理解是 不足以让我们预测NK细胞治疗操作的结果 反应我的研究重点是了解 控制先天性和适应性淋巴细胞发育，重点是E 蛋白螺旋-环-螺旋转录因子及其Id蛋白的拮抗剂。Id 2是 NK细胞发育的关键，但它如何发挥作用，以及是否需要适当的 NK细胞的成熟和功能仍然难以捉摸。 Id 2是成熟（m）NK细胞的终末成熟所需的，因此影响 NK细胞对病毒感染的反应，从而限制了NK细胞中的免疫记忆， 细胞群我们假设Id 2的功能是充分限制E蛋白的活性， 抑制其向备选淋巴细胞命运分化的潜力，但允许E 蛋白质激活T细胞相关信号蛋白的子集，这些信号蛋白是免疫应答中所需的。 mNK细胞亚群。我们将确定E 受Id 2抑制的蛋白质起改变NK谱系的命运和功能的作用 细胞我们的研究将使我们能够将E蛋白和Id 2的功能置于更大的 控制NK细胞发育和功能的转录调节因子网络， 将有助于我们了解治疗干预如何影响NK细胞 细胞反应。